α-Hydroxyketone compounds are found in natural products and frequently in the molecule framework of pharmaceutical compounds. They are synthetic equivalents for aldose compounds, e.g. pentoses and hexoses, and are very important synthetic building blocks which can lead to various physiologically active materials, medicines and intermediates in the synthesis of liquid crystalline materials.
α-Hydroxyketones can be obtained readily with high purity by asymmetric oxidation of carbonyl compounds. However, asymmetric oxidation of the α-position of the carbonyl group by the usual methods requires a two-step process. First, the preparation and isolation of an enolate, and second, the use of a relatively expensive oxygen-introducing reagent, which have the problem of low atom efficiency.
Other methods for direct preparation of chiral α-hydroxyketones without isolation of an enolate have been reported. These methods generally involve synthesizing enantioenriched α-aminooxyketones, which are precursors to α-hydroxyketones.
Previously disclosed were methods which used the amino acid proline as a catalyst and nitrosobenzene as an oxygen-introducing reagent to prepare α-aminooxyketones (see e.g. Brown, S. P., Brochu, M. P., Sinz, C. J. & MacMillan, D. W. C. (2003) J. Am. Chem. Soc. 125, 10808-10809; Zhong, G. (2003) Angew. Chem. Int. Ed. 42, 4247-4250; Hayashi, Y., Yamaguchi, J., Hibino, K. & Shoji, M. (2003) Tetrahedron Lett. 44, 8293-8296). However, many problems remain unsolved with this method, including a lack of catalytic efficiency (10 to 20 mol % catalyst is needed) and an inability to consistently reproduce results. Moreover, it is known that a second unwanted oxygen atom may be introduced via a side reaction with a second equivalent of nitrosobenzene.
Alternatively, it was reported that α-aminooxyketone could be obtained in high yield from an alkylsilyl ether and nitrosobenzene with alkylsilyl triflate as a Lewis Acid catalyst (see e.g. Momiyama, N., Yamamoto, H. (2002) Angew. Chem. Int. Ed. 41, 2986-2987) and also from an alkyltin enolate and nitrosobenzene with Ag-BINAP as a catalyst (see e.g. Momiyama, N., Yamamoto, H. (2003) J. Am. Chem. Soc. 125, 6038-6039).
Additionally, other methods have been disclosed to produce aldol products from the condensation reaction of carbonyl compounds by: (1) using a substrate with an ether or alcohol unit in the molecule with liquid CO2, or supercritical CO2 as a solvent (see e.g. Japanese Patent 2002- No. 284729); (2) running the reaction in water using boronic acid or a phase transfer catalyst or Brönsted acid (see e.g. Japanese Patent 2002-No. 275120); or (3) using a lanthanide triflate with a chiral crown ether (see e.g. Japanese Patent 2002-No. 200428).
Despite these methods for synthesizing α-aminooxyketone or α-hydroxyketone compounds, there is still a need in the art for a process which can produce α-aminooxyketone or α-hydroxyketone compounds with sufficient enantioselectivity, purity and/or reproducibility of results to enable these compounds to be suitable for use as synthetic building blocks or intermediates in a synthetic process.
One of the most intensely studied areas in chemical synthesis at present is the development of new enantioselective processes which are catalyzed by simple organic molecules. By using a proline-based chiral catalyst, we have discovered a reaction process which provides a method for the catalytic asymmetric synthesis of α-aminooxyketones via an O-nitroso Aldol reaction between an aldehyde or ketone and a nitroso compound. These compounds are easily converted into the synthetically important enatioenriched α-hydroxyketones.
Furthermore, we have developed a process for producing bicyclo ketones which contain nitrogen and oxygen heteroatoms via an asymmetric O-nitroso Aldol/Michael reaction between an α,β-unsaturated cyclic ketone with a nitroso compound. The product generated from this reaction is a Diels-Alder adduct that usually is formed through a typical Diels-Alder reaction. However, in the tandem O-Nitroso Aldol/Michael reactions described herein, the regiochemistry of the Diels-Alder adduct is opposite that of the normal nitroso Diels-Alder reaction. Owing to the ability to control both regiochemistry and stereochemistry, these catalytic asymeetric Aldol/Michael reactions provide novel routes to important or previously unaccessible heterocyclic compounds.
Citation or identification of any document in this application is not an admission that such document is available as prior art to the present invention.